Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection

Nat Immunol. 2013 Jun;14(6):574-83. doi: 10.1038/ni.2573. Epub 2013 Apr 14.

Abstract

Chronic infection is difficult to overcome because of exhaustion or depletion of cytotoxic effector CD8(+) T cells (cytotoxic T lymphoytes (CTLs)). Here we report that signaling via Toll-like receptors (TLRs) induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (iMATEs: 'intrahepatic myeloid-cell aggregates for T cell population expansion') without causing immunopathology. In the liver, CTL proliferation was restricted to iMATEs that were composed of inflammatory monocyte-derived CD11b(+) cells. Signaling via tumor-necrosis factor (TNF) caused iMATE formation that facilitated costimulation dependent on the receptor OX40 for expansion of the CTL population. The iMATEs arose during acute viral infection but were absent during chronic viral infection, yet they were still induced by TLR signaling. Such hepatic expansion of the CTL population controlled chronic viral infection of the liver after vaccination with DNA. Thus, iMATEs are dynamic structures that overcome regulatory cues that limit the population expansion of CTLs during chronic infection and can be used in new therapeutic vaccination strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • CD11b Antigen / immunology
  • CD11b Antigen / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Proliferation*
  • Chronic Disease
  • Flow Cytometry
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Host-Pathogen Interactions / immunology
  • Immunotherapy
  • Liver / immunology
  • Liver / metabolism
  • Liver / virology
  • Liver Diseases / immunology*
  • Liver Diseases / therapy
  • Liver Diseases / virology
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / therapy
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology
  • Lymphocytic choriomeningitis virus / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Confocal
  • Myeloid Cells / immunology*
  • Myeloid Cells / metabolism
  • Receptors, OX40 / immunology
  • Receptors, OX40 / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism
  • Toll-Like Receptor 9 / immunology
  • Toll-Like Receptor 9 / metabolism

Substances

  • CD11b Antigen
  • Receptors, OX40
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Green Fluorescent Proteins